US3252996A - Alpha-pyrrolidinomethyl valero and caprophenones - Google Patents

Alpha-pyrrolidinomethyl valero and caprophenones Download PDF

Info

Publication number
US3252996A
US3252996A US396352A US39635264A US3252996A US 3252996 A US3252996 A US 3252996A US 396352 A US396352 A US 396352A US 39635264 A US39635264 A US 39635264A US 3252996 A US3252996 A US 3252996A
Authority
US
United States
Prior art keywords
group
acid
formula
methyl
pyrrolidino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US396352A
Other languages
English (en)
Inventor
Huebner Charles Ferdinand
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF Corp
Novartis Corp
Original Assignee
Ciba Geigy Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to GB4391362A priority Critical patent/GB987281A/en
Application filed by Ciba Geigy Corp filed Critical Ciba Geigy Corp
Priority to US396352A priority patent/US3252996A/en
Priority to FR30856A priority patent/FR89312E/fr
Priority to BE669573D priority patent/BE669573A/xx
Priority to GB38938/65A priority patent/GB1062137A/en
Priority to FR39519A priority patent/FR5208M/fr
Application granted granted Critical
Publication of US3252996A publication Critical patent/US3252996A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms
    • C07D295/104—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/108—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/10—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by doubly bound oxygen or sulphur atoms

Definitions

  • the present invention concerns amino-ketones, or salts thereof. More especially, the invention relates to compounds of the formula:
  • the group of the formula (C I-l representing an alkyl group having from two to four carbon atoms is particularly ethyl or n-propyl, as well as isopropyl, n-butyl, isobutyl, secondary butyl and the like.
  • N,N-di-lower alkyl-amino representing the group Am is above all N,N-dimethylamino, as well as N-ethyl-N- methylamino, N,N-'diethylamino, N,N-di-n-propylamino and the like.
  • An N,N-alkylene-imino group, in which alkylene has from four to six carbon atoms, is usually l-pyrrolidino, as well as l-piperidino, 2-methyl-1-piperidino, 1-N,N-(l,6-hexylene)-imino and the like.
  • Salts of the compounds of this invention are acid addition salts, such as the pharmaceutically acceptable, nontoxic acid addition salts with inorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, with organic carboxylic acids, e.g. acetic, propionic, glycolic, lactic, succinic, maleic, hyd-roxymaleic, fumaric, :malic, tartaric, citric, glucuronic, benzoic, salicylic, 2-acetoxybenzoic, pamoic, nicotinic isonicotinic acid and the like, or with organic sulfonic acids, e.g.
  • inorganic acids e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like
  • organic carboxylic acids e.g. acetic, propionic, glycolic, lactic, succinic, maleic, hyd-roxy
  • acid addition salts may be used ⁇ as intermediates, for example, for the preparation of other acid addition salts, such as those having pharmaceutically acceptable properties, or in the purification of the free compound, or may be used for identification or characterization purposes.
  • Acid ad dition salts which are primarily used for the latter, for example, certain inorganic acids, e.g. perchloric acid and the like, with acidic organic nitro compounds, e.g. picric, picrolonic, flavianic acid and the like, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like.
  • the compounds may be in the form of mixtures of isomers or of the separated isomers.
  • the compounds of this invention produce an increase in coordinated motor activity in the unanesthetized dog, which effect is of considerable duration. They also antagonize sedation induced by administering tranquilizer-type sedatives; the antagonism becomes evident a Patented May 24, 1966 "ice short period after administration and is noticable over an appreciable period.
  • the compounds of this invention are useful stimulating agents to counteract excessive fatigue, lack of concentration, depressive states and the like, as well as in the treatment of barbiturate poisoning, or for the shortening of the recovery time after anesthesia. It has also been found, that the compounds of this invention have less toxic characteristics than known stimulating compounds.
  • the compounds of this invention are also useful as intermediates for the preparation of other pharmacologically active compounds. Upon reduction of the carbonyl group and, if desired, conversion of a resulting hydroxyl group into an esterified hydroxyl group according to methods described below, they are converted into compounds of the following formula:
  • Am and the radical of the formula (C H have the previously-given meaning, and R is hydrogen or the acyl radical of an organic carboxylic acid, or salts thereof.
  • the group R in the above formula which stands usually for hydrogen, may also be the acyl radical of a lower aliphatic carboxylic acid, such as, for example, a lower alkyl carbonic acid, e.g. methyl carbonic, ethyl carbonic acid and the like, carbamic acid, an N-lower alkyl-carbamic acid, e.g. N-methyl-ca-rbarnic, N-ethylcarbamic acid and the like, or, above all, a lower alkanoic acid, e.g.
  • acetic, propionic, butyric, pivalic acid and the like as well as any other suitable organic carboxylic acid, e.g. cyclohexane carboxylic, fi-cyclopentyl propionic, benzoic, 3,4,5-trimethoxybenzoic, phenylacetic, nicotinic, isonicotinic acid and the like.
  • These compounds also have stimulating properties, and, in addition, show analgesic effects; they are, therefore, useful as stimulants and/or as analgesics for the relief of pain.
  • Reduction of the carbonyl group is carried out according to conventional methods, for example, by treatment with a hydride reducive reagent, such as lithium aluminum hydride, sodium borohydride and the like, which reagents may be used in the presence of an activator, such as aluminum chloride and the like.
  • a hydride reducive reagent such as lithium aluminum hydride, sodium borohydride and the like
  • an activator such as aluminum chloride and the like.
  • Other methods suitable for the conversion of the carbonyl group into a carbinol group are, for example, treatment with certain metal lower alkoxides, e.g. aluminum isopropoxide and the like, which are used according to the Meerwein-Ponndorf-Verley method (A. L.
  • Particularly useful as central nervous system stimulants are the compounds of the formula:
  • m stands for the integer 1 or 2, or acid addition salts thereof, either in the form of their racemates or their optically active antipodes.
  • the compounds of this invention are prepared acin which the group of the formula (C,,H has the previously given meaning, with an amine of the formula HAm, in which Am has the previously-given meaning, or a salt thereof, in the presence of formaldehyde or a reactive derivative thereof, and, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into a salt thereof, and/ or, if desired, separating a mixture of isomers into the single isomers.
  • the above reaction of the starting material with the amine in the presence of formaldehyde or a reactive derivative thereof is carried out according to the procedure known as the Mannich Reaction, which is described, for example, in detail by F. F. Singhe in Organic Reactions, volume 1, page 303 (Wiley, 1942).
  • the salt of an amine of the formula HAm is an acid addition salt, particularly .the salt with a mineral acid, e.g. hydrochloric, hydrobromic, sulfuric acid and the like.
  • Reactive derivatives of formaldehyde are those furnishing formaldehyde under the conditions of the reaction; such derivatives are, for example, polymeric derivatives of formaldehyde, e.g.
  • reaction is preferably carried out in the presence of an inert solvent, for example, a lower alkanol, e.g. ethanol and the like, preferably at an elevated temperature, and, if necessary, in the presence of a small amount of an acid, such as a mineral acid, e.g. hydrochloric, sulfuric acid and the like, and/or, in a closed vessel, and/or, in the atmosphere of an inert gas, e.g. nitrogen.
  • an inert solvent for example, a lower alkanol, e.g. ethanol and the like, preferably at an elevated temperature, and, if necessary, in the presence of a small amount of an acid, such as a mineral acid, e.g. hydrochloric, sulfuric acid and the like, and/or, in a closed vessel, and/or, in the atmosphere of an inert gas, e.g. nitrogen.
  • the starting material are known and can be prepared according to per se conventional methods.
  • the compounds of this invention are also prepared by reacting a compound of the formula:
  • the reactive esterified hydroxyl group X stands primarily for halogeno (representing a hydroxyl group esterified with a hydrohalic acid), e.g. chloro, bromo and the like, as well as an organic sulfonyloxy group, e.g. p-toluene sulfonyloxy and .the like.
  • the above reaction between the reactive ester and the amine is carried out according to per se conventional methods, preferably by maintaining an excess of the amine, which may simultaneously serve as a base to neutralize the generated acid.
  • the latter may also be achieved by adding another alkaline reagent, e.g. sodium carbonate, potassium carbonate and the like.
  • the reaction is preferably completed at an elevated temperature, if desired, in the presence of an inert solvent, such as, for example, a lower alkanol, e.g. methanol, ethanol and the like, or any other suitable diluent, and/or, in a closed vessel, and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • an inert solvent such as, for example, a lower alkanol, e.g. methanol, ethanol and the like, or any other suitable diluent
  • the starting materials may be prepared accordance to methods known per se, for example, by introducing into the a-POSltiOIl of a compound of the formula:
  • the group of the formula (C H has the previously-given meaning, a carbon-lower alkoxy group, e.g. carbethoxy and the like (for example, by treatment of an alkali metal compound of the ketone with a lower alkyl orthoformate, e.g. ethyl orthoformate and the like) or a hydroxy-methylene group (for example, by treating an alkali metal compound of the ketone with a lower alkyl formate, e.g. ethyl formate and the like).
  • a carbon-lower alkoxy group e.g. carbethoxy and the like
  • a lower alkyl orthoformate e.g. ethyl orthoformate and the like
  • a hydroxy-methylene group for example, by treating an alkali metal compound of the ketone with a lower alkyl formate, e.g. ethyl formate and the like.
  • the carbo-lower alkoxy (if necessary, after hydrolysis to the free carboxyl group) or the hydroxy-methylene group is then converted into a hydroxy-methyl group by reduction, for example, by treat ment with a hydride reagent, e.g. lithium aluminum hydride and the like, or any other suitable reduction procedure, such as catalytic hydrogenation, electrolytic reduction and the like.
  • a hydride reagent e.g. lithium aluminum hydride and the like
  • the hydroxy-methyl group may also be introduced directly into the tat-position of the above starting material, for example, by reacting the latter with formaldehyde or a formaldehyde-furnishing.
  • reagent e.g. paraforrnaldehyde and the like
  • a suitable base e.g. sodium carbonate and the like.
  • the free hydroxyl group of the hydroxy-methyl portion of the resulting compound is then replaced by the desired reactive esterified hydroxyl group, for example, by halogeno (e.g. by treatment with a thionyl halide, e.g. thionyl chloride and the like, or a phosphorous halide, e.g. phosphorous tribromide and the like), or by an organic sulfonyloxy group (e.g. by esterification with an organic sulfonic acid halide, e.g. p-toluene sulfonic acid chloride and the like, preferably in the presence of a base, e.g. pyridine and the like).
  • halogeno e.g. by treatment with a thionyl halide, e.g.
  • the compounds of this invention may also by prepared, for vexample, by reacting a metal reagent of the formula:
  • M stands for the cation of certain metals of the group I-A of the Periodic System, or particularly for the cation of the formula HalMet in which Met stands for certain metals of the group lI-A of the Periodic System, and Hal stands for halogeno, with a compound of the formula:
  • a cation of metals of the group I-A of .the Periodic System, represented by M is that of certain alkali metals, particularly lithium, as well as sodium.
  • M is the group HalMet which stands primarily for Hal-Mg, in which Hal is halogeno, having an atomic weight greater than 35, e.g. chloro, bromo and the like.
  • each of the groups R and R which are preferably hydrogen may also be an organic radical, particularly lower alkyl, e.g. methyl,
  • reaction is carried out according to known methods, especially in the presence of an inert solvent, ifnecessary, at an elevated temperature and/or in the atmosphere of an inert gas, e.g. nitrogen.
  • an inert gas e.g. nitrogen.
  • the starting materials used in the above reaction are prepared according to known methods, for example, by reacting a compound of the formula:
  • Oxidation of the carbinol into the carbonyl group is carried out according to known methods, for example, by treatment with an oxidation reagent containing hexavalent chromium, e.g. potassium dichromate, chromium trioxide (for example, in the form of the complex with pyridine) and the like, with aluminum tertiary butanolate according to the Oppenauer oxidation reaction as described, for example, by C. Djerassi, Organic Reactions, volume 6, page 207 (Wiley, 1951), or any other oxidation method suitable for the conversion of a carbinol into a carbonyl group.
  • an oxidation reagent containing hexavalent chromium e.g. potassium dichromate, chromium trioxide (for example, in the form of the complex with pyridine) and the like
  • aluminum tertiary butanolate for example, by C. Djerassi, Organic Reactions, volume 6, page 207 (Wiley,
  • Y stands for a group of the formula CH -X in which X, is a reactive esterified hydroxyl group, or a carbinol group or a group capable of being converted into a carbinol group (such as a carbolower alkoxy group, e.g.
  • thionyl chloride and the like or with an organic sulfonyl halide, e.g. chloride and the like, according to the previously-shown procedure), and, if desired, converting in a resulting compound the secondary caribnol group adjacent to the phenyl group into an esterified carbinol group (according to known methods), for example, by treatment with an acid halide, e.g. chloride and the like, or an acid anhydride, if necessary, in the presence of a base, e.g. pyridine and the like.
  • a base e.g. pyridine and the like.
  • the starting materials used in the above oxidation procedure for the preparation of the ketone compounds of this invention may also be prepared, for example, by converting in a compound having the formula:
  • Am and the group of the formula (C,,H have the previously-given meaning, and Z stands for a carbinol group, an esterified carbinol group or a carbonyl group, the carbonyl group of the formula 0 0 into methylene, and, if necessary, converting in a resulting compound having a carbonyl group, such carbonyl group into a carbinol group.
  • a suitable hydride reagent e.g. lithium aluminum hydride and the like.
  • Z stands for a carbonyl group
  • such group may be reduced simultaneously to the desired carbinol group.
  • the starting materials used in the above reaction are prepared according to known methods, such as those previously-shown.
  • a carbonyl group Z is converted into the carbinol group using one of the previously described reduction methods, which do not attack the carbonyl of an amide grouping, such as, for example, treatment with hydrogen in the presence of a suitable catalyst, or with certain metal lower alkoxides, e.g. aluminum isopropoxide and the like (these methods have been previously outlined).
  • the carbinol starting materials used in the above oxidation procedure may also be prepared, for example, by reducing the aliphatic carbon-to-carbon double bond in a compound of the formula:
  • the carbinol compounds of the above formula may also be prepared by reacting a compound of the formula:
  • the compounds of this invention are obtained in the form of the free bases or the salts.
  • a resulting acid addition salt is converted into the free base, for example, by reacting it with a suitable hydroxyl ion exchange preparation, or with an alkaline reagent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia or any other suitable basic reagent.
  • a suitable hydroxyl ion exchange preparation or with an alkaline reagent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia or any other suitable basic reagent.
  • an alkaline reagent such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, a metal carbonate,
  • An acid addition salt is converted directly into another acid addition salt, for example, by reacting it with a suitable anion exchange preparation.
  • a salt with an inorganic acid may be reacted with a metal, e.g. sodium, barium, silver and the like, salt of an acid, preferably in the presence of a solvent, in which a resulting inorganic compound is insoluble and is thus removed from the reaction medium.
  • a resulting hydrobrornide may be converted into the maleate by treatment with the monosodium salt of maleic acid in a suitable diluent.
  • a free compound may be converted into an acid addition salt by reaction with one of the inorganic or organic acids described hereinbefore, for example, by treating a solution of the base in a suitable solvent with the acid or a solution thereof and isolating the desired salt.
  • the latter may also be obtained by reacting the free compound with a suitable anion exchange preparation. Salts may be obtained in the form of hydrates or may contain solvent of crystallization formation of the salts.
  • Compounds of this invention may be obtained as mixtures of isomers, which may be separated into the individual isomers.
  • racemates of the compounds of this invention may be resolved into the optically active dand lforms according to procedures used for the resolution of racemic compounds.
  • a solution of the free base of a racemic d,l-cmpound in an inert solvent may be treated with one of the optically active forms of an acid having at least one asymmetric carbon atom.
  • Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D-tartaric (l-tartaric) and L-tartaric (d-tartaric) acid, as well as the optically active forms of di-benZoyl-tartaric, di-o-tartaric, malic, mandelic, camphor -sulfonic, quinic acid and the like.
  • a resulting mixture of salts is then separated into the single salts, and,
  • the isolated salt may be converted into the optically active base according to known methods, such as those mentioned hereinabove; the optically active base may then be converted into its acid addition salts.
  • the invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is(are) carried out, as well as any new intermediates.
  • Example 1 A mixture of 78 g. of valerophenone, 5.38 g. of pyrrolidine hydrochloride, and 19.5 g. of paraformaldehyde in ml. of ethanol containing 1 ml. of concentrated hydrochloric acid is refluxed for twelve hours. The solvent is then evaporated, the residue is taken up in water, and the aqueous solution, after being extracted with diethyl ether, is made basic with aqueous ammonia. The organic material is extracted with diethyl ether, and the organic solution is dried over magnesium sulfate and evaporated. The residue is distilled to yield the cc-( l-pyrrolidino) -methyl-valerophenone of the formula:
  • N,N diethylaminomethyl valerophenone B.P. 100- 102/ 0.15 mm., which is prepared by reacting valerophenone with N,N-diethylamine hydrochloride in the presence of paraformaldehyde;
  • N,N dimethylaminomethyl valerophenone which is prepared by reacting valerophenone with N,N-dimethylamine in the presence of paraformaldehyde and which is converted into its hydrochloride salt, M.P. 157158, after recrystallization from a mixture of ethanol and diethyl ether;
  • a-(l-piperidino)-methyl-valerophenone B.P. l23125/ 0.3 mm., which is prepared by reacting valerophenone with piperidine hydrochloride in the presence of paraformaldehyde,
  • the above compounds may be used as starting materials for the preparation of the corresponding carbinol compounds, for example, according to the following procedure: To a solution of 11.0 g. of a-(1-pyrrolidino)- methyl-valerophenone in 100 ml. of ethanol is added in small portions 4.75 g. of sodium borohydride. The reaction mixture is refluxed for four hours; the solvent is evaporated and the residue is treated with water. The organic material is extracted with diethyl ether, the organic solution is dried over magnesium sulfate and evaporated. The residue is distilled to give the l-phenyl-2- (l-pyrrolidino)-methyl-l-pentanol, which boils at 128- 130/0.5 mm.; yield: 6.0 g.
  • Example 2 To a solution of 66.0 g. of u-(l-pyrrolidino)-methylvalerophenone in diethyl ether is added an excess of a 9 7.5 N solution of hydrogen chloride in ethanol. The resulting precipitate is filtered off, washed with diethyl ether and recrystallized from ethanol, to yield the m-(lpyrrolidino)-methyl-valerophenone hydrochloride, M.P. 141144.
  • Example 3 A mixture of 17.6 g. of caprophenone, 10 ml. of pyrrolidine, 17 ml'. of 6 N ethanolic hydrogen chloride, 5.9 g. of paraformaldehyde and 20 ml. of ethanol is refluxed for twelve hours. The solvent is evaporated and the residue is taken up in 100 ml. of water; the insoluble material is filtered off and the aqueous solution is made basic with aqueous ammonia. The organic material is extracted with diethyl ether, the organic solution is separated, dried and evaporated, and the residue is distilled to yield the a-(l-pyrrolidino) -methyl-caprophenone of the C HzCH2- H2 a B.P. 168-172/ 1.0 mm., which is converted into its hydrochloride, M.P. 1414 44 after recrystallization from ethanol, according to the procedure described in Example 2.
  • the a-(l-pyrrolidino)-rnethyl-caprylophenone is obtained by reacting caprylophenone with pyrrolidine and paraformaldehyde in the presence of hydrochloric acid and ethanol according to the above procedure.
  • Example 5 To a solution of 53.8 ml. of pyrrolidine in 127 ml. of a 6 N ethanol solution of hydrogen chloride are added 57 g. of dimethoxymethane, 100.0 g. of valerophenone, 1.1 ml. of concentrated hydrochloric acid and 25 ml. of ethanol. The reaction mixture is refluxed for twelve hours; the solvent is then evaporated under reduced pressure, and the residue is diluted with water. The unreacted valerophenone is extracted with diethyl ether; the aqueous layer is made basic with ammonium hydroxide and the organic basic material is extracted with diethyl ether. The organic solution is dried over sodium sulfate and evaporated to yield the u-(1-pyrrolidino)- methyl-valerophenone, which is purified by distillation and collected at 121-124/0.07 mm.
  • Example 6 The crude whydroxymethyl-valerophenone p-toluene sulfonic acid ester (prepared according to the procedure described herein below) and 20.0 g. of pyrrolidine in ml. of ethanol are refluxed, and the solvents are then evaporated under reduced pressure; the residue is treated with an aqueous solution of ammonia and the organic material is extracted with diethyl ether. The organic solution is separated, dried over sodium sulfate and evaporated. The residue is distilled, B.P. 132 136/0.7 mm., to yield the desired CAI-pyrrolidine)- methyl-valerophenone, which is converted into its hydrochloride, M.P. 141-144, according to the procedure de scribed in Example 2.
  • the starting material used in the above procedure is prepared as follows: A suspension of 50.0 g. of valerophenone and 11.0 g. of paraformaldehyde in 500 ml. of water containing 1.0 g. of sodium carbonate is stirred for 48 hours. The solid u-hydroxymethyl-valerophenone is filtered off and 25.0 g. of this material is dissolved in 100 ml. of pyridine; the solution is treated with 30.0 g. of p-toluene sulfonic acid chloride. After standing for 24 hours, the mixture is poured into ice water and the ot-hydroxymethyl-valerophenone p-toluene sulfonic acid ester is filtered off.
  • the a-hydroxymethyl-valerophenone p-toluene sulfonic acid ester may be replaced by a-chloromethyl-valerophenone or by a-bromomethylvalerophenone; by refluxing the latter with pyrrolidine in the presence of ethanol, they are converted into the desired a-(l-pyrrolidino)-methylvalerophenone.
  • the starting materials are prepared by reacting the u-hydroxymethyl-valerophenone with one mol of thionyl chloride in refluxing chloroform or with phosphorous tribromide, pouring the resulting compound into ice water and isolating the desired a-halogeno-methyl-valerophenone compound.
  • Example 7 To a mixture of 25.0 g. of 1-phenyl-2-(l-pyrrolidino)- methyl-n-pentanol in 100 ml. of pyridine is added slowly 12.2 g. of Sarretts reagent (chromium trioxide-pyridine complex) while externally cooling to maintain room temperature. After twelve hours, the pyridine is distilled off under reduced pressure; the residue is diluted with water and treated with an aqueous solution of ammonium hydroxide. The organic material is extracted, the organic solution is separated, dried and evaporated, and the residue is distilled to yield the u-(l-pyrrolidine)-rnethylvalerophenone, B.P. 132136/O.7 mm., which is converted into its crystalline hydrochloride, M.P. 141-144", according to the method described in Example 2.
  • Sarretts reagent chromium trioxide-pyridine complex
  • the starting material used in the above procedure is prepared as follows: A solution of 100.0 g. of a a-(npropyl)-acrolein in 500 ml. of absolute ethanol is saturated with hydrogen chloride while maintaining a temperature of 0. After two days standing at room temperature, the solvent is removed and the ec-chloromethyh valeraldehyde diethylacetal is distilled under reduced pressure. A mixture of 50.0 g. of ct-chloromethyl-valeraldehyde and 35.0 g. of pyrrolidine in 200 ml. of ethanol is refluxed for twelve hours.
  • the solvent is removed under reduced pressure and the residue is dissolved in water; the aqueous mixture is made basic with ammonium hydroxide and is extracted with diethyl ether.
  • the desired a-(l-pyrrolidino) methyl valeraldehyde diethylacetal is purified by distilling the residue of the diethyl ether extract.
  • a solution of 50.0 g. of a-(1-pyrrolidino)-methyl-valeraldehyde diethyla-cetal in 250 ml. of 2 N aqueous hydrochloric acid is allowed to stand for three days.
  • the solution is then made basic and the a-(1-pyrrolidino)-methyl-valeraldehyde is extracted with 200 ml. of anhydrous diethyl ether. After drying over magnesium sulfate, this ether solution is added to a Grignard reagent, prepared from 34.0 g. of bromobenzene and 5.5 g. of magnesium in 200 ml. of diethyl ether.
  • the reaction mixture is cooled and treated with ml. of a saturated aqueous solution of ammonium chloride; the organic layer is separated and washed with dilute aqueous hydrochloric acid.
  • the combined acidic washings are rendered basic with aqueous ammonia; the organic material is extracted wtih diethyl ether and the desired 1phenyl-2-(l-pyrrolidino)-methyl-n-pentanol is isolated by separating, drying and evaporating the organic solution and distilling the residue; the desired product boils at l28l30/ 0.5 mm., and is identical with the product obtained according to the procedure of Example 1.
  • Example 8 To a Grignard reagent, prepared by reacting 62.0 g. of bromobenzene and g. of magnesium in 500 ml. of diethyl ether and initiating the reaction by adding a small amount of crystalline iodine, is added a diethyl ether solution of o-(l-pyrrolidino)-methyl-valeric acid amide as prepared according to the procedure described below. The reaction mixture is refluxed for twelve hours, and is then cooled and treated dropwise with 200 ml. of a saturated aqueous solution of ammonium chloride. The diethyl ether solution is separated, and extracted with dilute aqueous hydrochloric acid.
  • the combined aqueous extracts are made basic with an aqueous solution of ammonia, and the organic material is extracted with diethyl ether. The organic solution is separated, dried over sodium sulfate and evaporated. The residue is distilled, B.P. 132-l36/0.7 mm., to yield the desired u-(l-pyrrolidino)-methyl-valerophenone, which is converted into its hydrochloride, M.P. 141- -144, according to the procedure described in Example 2.
  • the starting material used in the above procedure may be prepared as follows: To a solution of 50.0 g. of methyl a-propylacrylate in 200 ml. of ethanol containing 1 ml. of a 30 percent solution of benzyl trimethyl ammonium hydroxide, is added 28.0 g. of pyrrolidine while externally cooling. After reacting for six hours at room temperature, the reaction mixture is saturated with dry ammonia and is allowed to stand at room temperature for one week. The solvent is distilled off under reduced pressure to yield the crude a-(1-pyrrolidino)-methyl-valeric acid amide, which is purified by dissolving it in 100 ml. of anhydrous diethyl ether, washing the organic solution twice with water and drying over magnesium sulfate, and used without further isolation.
  • Example 9 The compounds of this invention may be used in the form of compositions for enteral or parenteral use, which contain the new compounds in admixture with an organic or inorganic, solid or liquid carrier. These preparations are manufactured according to known methods, and car rier materials are employed which do not react with the new com-pounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talcum, vegetable oils, benzyl alcohol, gums, tragacanth, propylene glycol, polyalkylene glycols or any other carrier useful for the preparation of compositions.
  • car rier materials are employed which do not react with the new com-pounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talcum, vegetable oils, benzyl alcohol, gums, tragacanth, propylene glycol, polyalkylene glycols or any other carrier useful
  • the latter may be in solid form, for example, as capsules, tablets, and the like, or in liquid form, for example, as solutions, suspensions, emulsions, and the like. If desired, they may contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying, coloring, flavoring agents, and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances.
  • compositions included within the scope of this invention contain from about one percent to about fifty percent of a compound of the formula:
  • compositions for oral administration contain from about 0.005 g. to about 0.05 g., preferably from about 0.01 g. to about 0.03 g. of one of the above compounds, especially of a compound of the formula:
  • Tablets containing 0.02 g. of a-(1-pyrrolidino)-methylvalerophenone hydrochloride are prepared as follows (for 1,000,000 tablets) Ingredients:
  • the a-(l-pyrrolidino)-methyl-valerophenone hydrochloride and the tragacanth are passed through a Fitzpatrick mill, set at low speed, knives forward and using a No. 1 Type A screen.
  • the D & C Orange No. 3 is triturated with 3,000 g. of lactose, previously-screened through a No. 16 sieve. 120,980 g. of lactose is screened through a No. 16 sieve and is placed into a mixer; the color triturate, the mixture of the a-(1-pyrrolidino)-methylvalerophenone hydrochloride and the tragacanth, and the confectioners sugar (previously passed through a No.
  • the wet granules are passed through a Fitzpatrick mill set at low speed, knives forward and using a No. 4 Type A screen.
  • the product is spread on trays and dried for about two and one-half hours at 433 using circulating dehumidified air; the moisture content of the dried product is between about 2.5 percent minimum and 3 percent maximum.
  • the granules are then passed through a Fitzpatrick mill, set at medium speed, knives forward and using a No. 2 Type A screen.
  • the granules are placed into a mixer and the talcum, corn starch and magnesium stearate used as the lubricants are added through a No. 16 screen. Mixing is maintained for twenty minutes, at high speed, and the granules are compressed into tablets weighing 0.2 g. each, using 10/ 32 inch shallow concave punches.
  • Capsules containing 0.01 g. of (l)-a-(1-pyrrolidino)- methyl-valerophenone hydrochloride are prepared as follows (for 10,000 capsules):

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
US396352A 1961-11-20 1964-09-14 Alpha-pyrrolidinomethyl valero and caprophenones Expired - Lifetime US3252996A (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
GB4391362A GB987281A (en) 1961-11-20 1962-11-20 Basic ketones and process of preparing same
US396352A US3252996A (en) 1962-10-02 1964-09-14 Alpha-pyrrolidinomethyl valero and caprophenones
FR30856A FR89312E (fr) 1962-10-02 1965-09-09 Procédé de préparation de nouvelles cétones basiques, entre autres de l'alpha-(pyrrolidino-méthyl)-valérophénone
BE669573D BE669573A (enrdf_load_stackoverflow) 1962-10-02 1965-09-13
GB38938/65A GB1062137A (en) 1962-10-02 1965-09-13 Optically active -a-(pyrrolidino-methyl)-valerophenone and process for its manufacture
FR39519A FR5208M (enrdf_load_stackoverflow) 1962-10-02 1965-11-24

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US22771262A 1962-10-02 1962-10-02
US396352A US3252996A (en) 1962-10-02 1964-09-14 Alpha-pyrrolidinomethyl valero and caprophenones

Publications (1)

Publication Number Publication Date
US3252996A true US3252996A (en) 1966-05-24

Family

ID=26921689

Family Applications (1)

Application Number Title Priority Date Filing Date
US396352A Expired - Lifetime US3252996A (en) 1961-11-20 1964-09-14 Alpha-pyrrolidinomethyl valero and caprophenones

Country Status (4)

Country Link
US (1) US3252996A (enrdf_load_stackoverflow)
BE (1) BE669573A (enrdf_load_stackoverflow)
FR (1) FR5208M (enrdf_load_stackoverflow)
GB (1) GB1062137A (enrdf_load_stackoverflow)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3499033A (en) * 1967-01-06 1970-03-03 Upjohn Co Ethers of alpha-phenyl-2-aminocycloalkanemethanols
US4638009A (en) * 1984-01-26 1987-01-20 Hokuriku Pharmaceutical Co., Ltd. Derivatives of 3-pyrrolidinopropiophenone and a process for preparation thereof
US20070293499A1 (en) * 2006-05-18 2007-12-20 Mannkind Corporation Intracellular Kinase Inhibitors
US20090186893A1 (en) * 2007-06-08 2009-07-23 Mannkind Corporation IRE-1alpha INHIBITORS

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide
US2778853A (en) * 1952-09-10 1957-01-22 Merck & Co Inc Deamination process
US3000946A (en) * 1958-03-18 1961-09-19 Ciba Pharm Prod Inc beta-amino-alpha-bromo-propiophenones

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US1915334A (en) * 1930-10-16 1933-06-27 Du Pont Fluosilicate of organic heterocyclic bases and process of making it
US2075359A (en) * 1930-10-16 1937-03-30 Du Pont Insecticide
US2778853A (en) * 1952-09-10 1957-01-22 Merck & Co Inc Deamination process
US3000946A (en) * 1958-03-18 1961-09-19 Ciba Pharm Prod Inc beta-amino-alpha-bromo-propiophenones

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3499033A (en) * 1967-01-06 1970-03-03 Upjohn Co Ethers of alpha-phenyl-2-aminocycloalkanemethanols
US4638009A (en) * 1984-01-26 1987-01-20 Hokuriku Pharmaceutical Co., Ltd. Derivatives of 3-pyrrolidinopropiophenone and a process for preparation thereof
US20070293499A1 (en) * 2006-05-18 2007-12-20 Mannkind Corporation Intracellular Kinase Inhibitors
US8604031B2 (en) 2006-05-18 2013-12-10 Mannkind Corporation Intracellular kinase inhibitors
US20090186893A1 (en) * 2007-06-08 2009-07-23 Mannkind Corporation IRE-1alpha INHIBITORS
US7858666B2 (en) 2007-06-08 2010-12-28 Mannkind Corporation IRE-1α inhibitors
US20110065162A1 (en) * 2007-06-08 2011-03-17 Mannkind Corporation IRE-1alpha INHIBITORS
US8614253B2 (en) 2007-06-08 2013-12-24 Mannkind Corporation IRE-1α inhibitors
US9241942B2 (en) 2007-06-08 2016-01-26 Mannkind Corporation IRE-1α inhibitors
US9546149B2 (en) 2007-06-08 2017-01-17 Mannkind Corporation IRE-1α inhibitors
US9981901B2 (en) 2007-06-08 2018-05-29 Fosun Orinove Pharmatech, Inc. IRE-1α inhibitors

Also Published As

Publication number Publication date
FR5208M (enrdf_load_stackoverflow) 1967-07-03
BE669573A (enrdf_load_stackoverflow) 1966-03-14
GB1062137A (en) 1967-03-15

Similar Documents

Publication Publication Date Title
US3931195A (en) Substituted piperidines
DE69704679T2 (de) 4-phenylpiperidin-derivate
US3522319A (en) Phenol substituted tetrahydronaphthalenes useful as estrogenics
US3151124A (en) Alpha oxy-beta alkyl-gamma tertiary amino-alpha phenyl propanes
US3203962A (en) Alpha-phenyl-beta pyrrolidino-propiophenones
DE2408476C2 (enrdf_load_stackoverflow)
US3252996A (en) Alpha-pyrrolidinomethyl valero and caprophenones
DE2537837A1 (de) Tetrahydropyridin- und piperidinderivate und verfahren zu ihrer herstellung
US3072716A (en) Substituted indenes
US2355659A (en) Piperidine derivatives and process for the manufacture of the same
EP0065295A1 (de) Substituierte Tryptaminderivate von Thienyloxypropanolaminen, Verfahren zu ihrer Herstellung, pharmazeutische Präparate auf Basis dieser Verbindungen sowie ihre Verwendung
US3328411A (en) Novel piperidine derivatives
US3250767A (en) 1, 1, 2 triaryl ethanes, ethenes and ethanols
DE1936206A1 (de) Diphenylmethoxyaethylaminoderivate und Verfahren zu ihrer Herstellung
US3234211A (en) Tertiaryaminoalkoxy alkylene monocyclic carbocyclic aryltetrahydro naphthalenes, indanes, indenes and homologs thereof
US3646122A (en) Decahydronaphthyl substituted phenoxyaliphatic acids
CH619220A5 (enrdf_load_stackoverflow)
US3374245A (en) Unsaturated oxacycles
JPH037280A (ja) 新規ベンゾチオピラニルアミン
US3076804A (en) 2-(n, n-di-loweralkyl-amino-loweralkyl)-1-[pyridyl-methylidene]-indene and process
US4000274A (en) Pharmaceutical compositions containing an n-aryl-n'-(phenyl-or-phenoxy-alkyl)-piperazine and method of use
US4006184A (en) 1- OR 2-[2-Hydroxy-3-amino-propoxy]-9,10-dihydro-9,10-ethano-anthracenes and their salts
AT319936B (de) Verfahren zur Herstellung von neuen Phenylimidazolidinonderivaten und ihren Salzen
US3483209A (en) Aralkylamines
US3998965A (en) 4-Aminoalkyl-4-cyano-4-phenyl-butanoic acid esters